Cagrilintide

Research Use Only: This page is for research and educational purposes only. It does not provide medical advice, treatment instructions, or guaranteed outcome claims.

What Is Cagrilintide?

Cagrilintide is a synthetic, long-acting amylin analog designed to mimic and extend the physiological actions of native human amylin. In healthy physiology, amylin is co-released with insulin after meals and acts on brainstem receptors — particularly the area postrema and nucleus tractus solitarius — to promote satiety, slow gastric emptying, and suppress post-meal glucagon secretion.[1][5]

The problem with native amylin is its extremely short half-life (approximately 13 minutes) and a tendency to aggregate into amyloid fibrils, making it impractical as a therapeutic agent. Cagrilintide overcomes both limitations through strategic modifications: the attachment of a C18 fatty diacid chain via a glutamic acid linker enables reversible albumin binding, dramatically extending its circulating half-life to approximately 160–195 hours and supporting once-weekly subcutaneous administration.[1][6]

The compound was previously known by its research code AM833 during early development. It activates both the calcitonin receptor (CTR) and the amylin receptor subtypes (AMY1, AMY2, AMY3), which are heterodimers of the calcitonin receptor with receptor activity-modifying proteins (RAMPs).[2] This receptor pharmacology distinguishes cagrilintide from GLP-1 based therapies like semaglutide and tirzepatide, which act on entirely different receptor systems.

Compound Profile

Mechanism of Action

Understanding the cagrilintide mechanism of action requires appreciating how amylin signalling differs from — and complements — the incretin pathway.

Central appetite regulation. Cagrilintide acts as a potent long-acting amylin receptor agonist, binding to amylin receptors (AMY1–3) concentrated in the area postrema and hypothalamic nuclei. Activation of these receptors reduces food intake through direct neuronal signalling, independent of the GLP-1 pathway. The area postrema sits outside the blood-brain barrier, allowing circulating cagrilintide direct access to these satiety centres.[2][5]

Calcitonin receptor activation. In addition to amylin receptor subtypes, cagrilintide activates the calcitonin receptor (CTR) itself. In vitro pharmacological profiling confirmed that AM833 (cagrilintide) is a potent agonist at all three AMY receptor subtypes and at CTR, with a preference for AMY1 and AMY3. This dual calcitonin and amylin receptor agonism (DACRA) may contribute to its weight-lowering effects through additional signalling pathways beyond classical amylin action.[2]

Gastric motility. Like native amylin, cagrilintide slows gastric emptying, prolonging nutrient contact with the gastrointestinal mucosa and contributing to post-meal satiety. This effect is mechanistically distinct from, but additive to, the gastric-slowing properties of GLP-1 agonists.[5][9]

Glucagon suppression. Cagrilintide suppresses post-prandial glucagon secretion from pancreatic alpha cells. By reducing inappropriate glucagon release after meals, the compound helps moderate hepatic glucose output — a mechanism relevant to glycaemic control in type 2 diabetes research.[5][7]

The complementary nature of these mechanisms explains the rationale behind CagriSema: cagrilintide engages brainstem amylin pathways while semaglutide engages hypothalamic and peripheral GLP-1 pathways. The two receptor systems converge on overlapping but distinct neuronal populations controlling energy intake and expenditure.[4][9]

CagriSema: Combination Research

CagriSema — the co-administration of cagrilintide 2.4 mg and semaglutide 2.4 mg once weekly — is the centrepiece of Novo Nordisk’s next-generation obesity pipeline and arguably the most significant cagrilintide semaglutide combination programme in metabolic research. The hypothesis: engaging two distinct satiety pathways (amylin + GLP-1) simultaneously should produce greater weight loss than either mechanism alone.

Phase 1b Proof of Concept

The initial pharmacokinetic and pharmacodynamic study (Enebo et al., 2021) demonstrated that concomitant administration of cagrilintide with semaglutide 2.4 mg was well-tolerated and produced additive weight reductions over 20 weeks. Participants receiving the combination achieved significantly greater body weight loss than semaglutide alone, establishing the proof of concept for dual amylin–GLP-1 agonism.[4]

Phase 2 in Type 2 Diabetes

Frias et al. (2023) published a multicentre, randomised, double-blind trial evaluating CagriSema in adults with type 2 diabetes. Over 32 weeks, cagrilintide 2.4 mg co-administered with semaglutide 2.4 mg produced a mean HbA1c reduction of 2.2 percentage points and a mean body weight reduction of 15.6% — substantially exceeding the effects of semaglutide 2.4 mg monotherapy (5.1% weight loss) and cagrilintide 2.4 mg monotherapy (8.1% weight loss) in the same trial.[7]

REDEFINE Phase 3 Programme

The pivotal Phase 3 data arrived in 2025 with two landmark New England Journal of Medicine publications:

REDEFINE 1 (Garvey et al., 2025): In adults with overweight or obesity without type 2 diabetes, CagriSema produced a mean body weight reduction of approximately 22.7% at 68 weeks, compared to approximately 16.2% for semaglutide 2.4 mg alone and 8.0% for cagrilintide 2.4 mg alone. The proportion of participants achieving ≥20% weight loss was substantially higher in the CagriSema arm.[3]

REDEFINE 2 (Davies et al., 2025): In adults with overweight or obesity and type 2 diabetes, CagriSema demonstrated a mean body weight reduction of approximately 15.7% at 68 weeks, compared to approximately 11.0% for semaglutide 2.4 mg alone. Mean HbA1c reductions with CagriSema reached approximately 2.2 percentage points.[8]

These results position CagriSema as potentially the most effective injectable weight management combination studied in Phase 3 trials to date, exceeding the benchmarks set by semaglutide 2.4 mg (STEP trials) and approaching the territory of tirzepatide (SURMOUNT trials).

Weight Loss Clinical Data

Beyond the CagriSema combination, cagrilintide weight loss data from monotherapy trials provides important context for understanding the amylin pathway’s independent contribution.

Phase 2 Monotherapy Trial

Lau et al. (2021) published a 26-week, multicentre, randomised, double-blind Phase 2 trial comparing multiple cagrilintide doses against placebo and liraglutide 3.0 mg as an active comparator in adults with overweight or obesity. Key findings:[6]

• Cagrilintide at the highest tested doses produced mean body weight reductions of 10.8% (4.5 mg) at 26 weeks
• The 2.4 mg dose — the dose carried forward into CagriSema — produced approximately 9.0% weight loss
• Liraglutide 3.0 mg (daily injection) produced 9.0% weight loss in the active comparator arm
• Placebo produced approximately 3.0% weight loss
• Weight loss curves had not plateaued at 26 weeks, suggesting greater reductions with longer treatment

These results established cagrilintide as a viable standalone weight management research compound, with efficacy comparable to liraglutide 3.0 mg but via a once-weekly injection. However, the real significance was its additive potential when combined with GLP-1 agonism — the foundation of the CagriSema programme.

Metabolic Effects Beyond Weight Loss

The metabolic profile of cagrilintide extends beyond body weight reduction, touching several parameters relevant to cardiometabolic research.

Glycaemic control. In participants with type 2 diabetes, CagriSema produced substantial HbA1c reductions (approximately 2.2 percentage points in REDEFINE 2), with a significant proportion reaching HbA1c targets below 7.0% and below 6.5%. Cagrilintide’s glucagon-suppressive properties contribute to post-prandial glucose control independently of the GLP-1 pathway.[7][8]

Cardiovascular biomarkers. The REDEFINE 1 trial showed improvements in blood pressure, waist circumference, and lipid profiles with CagriSema treatment. A pre-specified analysis (Verma et al., 2026) demonstrated clinically meaningful systolic blood pressure reductions in the CagriSema arm, independent of weight loss magnitude.[10]

Insulin sensitivity. Weight loss mediated by cagrilintide — whether alone or in combination — is associated with improvements in insulin sensitivity markers, including fasting insulin and HOMA-IR. These effects are likely secondary to reduced adiposity rather than direct insulin-sensitising action, but they reinforce the metabolic relevance of the amylin pathway.[6][7]

Body composition. While detailed body composition data (DXA-based) from the REDEFINE programme are still emerging, the magnitude of weight loss with CagriSema suggests significant fat mass reduction. Research into the proportion of lean versus fat mass lost will be critical for understanding the compound’s metabolic quality profile.

Side Effects and Safety Profile

The safety profile of cagrilintide has been characterised across Phase 1 through Phase 3 trials, both as monotherapy and in the CagriSema combination.

Gastrointestinal events. The most common adverse events are gastrointestinal: nausea, vomiting, diarrhoea, and constipation. These are generally mild to moderate in severity, occur primarily during dose escalation, and tend to diminish with continued treatment. In the REDEFINE trials, discontinuation rates due to adverse events were comparable between CagriSema and semaglutide arms.[3][8]

Injection site reactions. As a subcutaneous injection, cagrilintide is associated with mild injection site reactions in a small proportion of study participants. These are typically transient and do not require treatment discontinuation.[6]

Cardiac safety. A dedicated thorough QT study (Gabe et al., 2024) confirmed that cagrilintide at therapeutic and supratherapeutic exposures does not produce clinically relevant QTc prolongation — an important regulatory milestone for any cardiovascular safety evaluation.[9]

Hypoglycaemia. In participants without type 2 diabetes, clinically significant hypoglycaemia has not been a notable finding. In participants with type 2 diabetes receiving concomitant insulin or sulfonylureas, rates of hypoglycaemia are modestly elevated, as would be expected with any weight-lowering agent in this population.[7][8]

Pancreatic and thyroid safety. Like GLP-1 agonists, amylin analogs carry theoretical signals for pancreatitis and thyroid C-cell concerns. Clinical trial data to date have not identified a significant safety signal for pancreatitis with cagrilintide. Long-term post-marketing surveillance data are not yet available as the compound remains investigational.[3][6]

Pharmacokinetics

The pharmacokinetic profile of cagrilintide is engineered for once-weekly administration, achieved through its albumin-binding acylation strategy.[1]

Half-life. Cagrilintide has an elimination half-life of approximately 160–195 hours (roughly 7–8 days), supporting steady-state concentrations with once-weekly subcutaneous injection. This represents a dramatic extension over native amylin’s 13-minute half-life.[1][6]

Albumin binding. The C18 fatty diacid modification enables reversible, high-affinity binding to serum albumin. This albumin depot effect slows renal clearance and proteolytic degradation, maintaining therapeutic exposure throughout the dosing interval. The mechanism is analogous to the acylation strategy used for semaglutide and liraglutide, though the fatty acid and linker structures differ.[1]

Absorption. Following subcutaneous injection, cagrilintide exhibits a slow absorption profile with time to maximum concentration (T_max) of approximately 24–72 hours. Bioavailability is consistent across injection sites (abdomen, thigh, upper arm).[1][6]

Drug interaction potential. In the CagriSema programme, no clinically meaningful pharmacokinetic interactions were observed between cagrilintide and semaglutide when co-administered. Each compound maintains its independent pharmacokinetic profile, supporting the combination approach.[4]

Steady state. Given the approximately one-week half-life, steady-state concentrations are reached after approximately 4–5 weeks of weekly administration. Dose escalation protocols in clinical trials typically span 16 weeks to mitigate gastrointestinal tolerability during the early treatment phase.[3][6]

Amylin Biology and the Rationale for Cagrilintide

To fully appreciate cagrilintide’s therapeutic positioning, it helps to understand the biology of the amylin system it targets.

Amylin (also known as islet amyloid polypeptide, or IAPP) is a 37-amino-acid peptide hormone produced by pancreatic beta cells and co-secreted with insulin in response to nutrient intake. Its physiological roles include:

• Satiety signalling — via amylin receptors in the area postrema, reducing meal size and food intake
• Gastric emptying regulation — slowing nutrient delivery to the small intestine
• Post-prandial glucagon suppression — reducing hepatic glucose output after meals

In obesity and type 2 diabetes, amylin signalling is often impaired. Beta cell dysfunction reduces amylin secretion, and amylin resistance may develop in the central nervous system. This creates a rationale for exogenous amylin replacement or supplementation — the strategy that cagrilintide fulfils as a potent, long-acting amylin analog.[5][9]

The first amylin-based therapy, pramlintide (Symlin), was approved in 2005 but required three daily injections and produced only modest weight effects. Cagrilintide represents the next generation: once-weekly dosing, greater potency, and clinically meaningful weight reduction potential.[5][9]

FAQ

What is cagrilintide?

Cagrilintide is a long-acting synthetic analog of human amylin, a pancreatic hormone involved in satiety and glucose regulation. Developed by Novo Nordisk under the research code AM833, it is designed for once-weekly subcutaneous injection and is currently under investigation in Phase 3 clinical trials for weight management research. It is not approved for clinical use.

How does cagrilintide differ from GLP-1 receptor agonists like semaglutide?

Cagrilintide targets the amylin receptor system in the brainstem, while GLP-1 agonists like semaglutide act on the GLP-1 receptor in the hypothalamus and periphery. These are complementary but mechanistically distinct satiety pathways. This is precisely why the CagriSema combination (cagrilintide + semaglutide) is being studied — to engage both pathways simultaneously for potentially greater effect.

What is CagriSema?

CagriSema is the co-administration of cagrilintide 2.4 mg and semaglutide 2.4 mg, both given once weekly. It is Novo Nordisk’s next-generation combination therapy under investigation in the REDEFINE Phase 3 programme for obesity and type 2 diabetes. The combination targets two distinct hormone pathways (amylin + GLP-1) and has produced weight reductions of approximately 22.7% in Phase 3 trials.

What weight loss has been observed in cagrilintide clinical trials?

In Phase 2 monotherapy, cagrilintide 2.4 mg produced approximately 9% body weight loss at 26 weeks. In the Phase 3 REDEFINE 1 trial, CagriSema produced approximately 22.7% weight loss at 68 weeks, compared to 16.2% for semaglutide 2.4 mg alone. In REDEFINE 2 (type 2 diabetes), CagriSema achieved approximately 15.7% weight loss at 68 weeks. These are investigational data from clinical trials.

What is the mechanism of action of cagrilintide?

Cagrilintide acts as a potent agonist at amylin receptor subtypes (AMY1, AMY2, AMY3) and the calcitonin receptor (CTR). These receptors are concentrated in the area postrema and hypothalamic nuclei, where activation reduces food intake, slows gastric emptying, and suppresses post-prandial glucagon secretion. The compound’s acylation with a C18 fatty diacid enables albumin binding and a half-life of approximately 160–195 hours.

Is cagrilintide approved by the FDA or other regulators?

No. As of early 2026, cagrilintide remains an investigational compound. It is in Phase 3 clinical trials (the REDEFINE programme) for obesity and type 2 diabetes, both as monotherapy and as the CagriSema combination. Regulatory submissions have not yet been completed. All data should be interpreted in a research context only.

What are the main side effects observed in cagrilintide trials?

The most commonly reported adverse events are gastrointestinal: nausea, vomiting, diarrhoea, and constipation. These are generally mild to moderate, peak during dose escalation, and tend to resolve with continued treatment. A thorough QT study confirmed no clinically relevant cardiac conduction effects. The safety profile is broadly consistent with other peptide-based metabolic compounds.

How does CagriSema compare to tirzepatide for weight loss?

Direct head-to-head comparison data between CagriSema and tirzepatide are not available from randomised trials. In separate Phase 3 programmes, CagriSema produced approximately 22.7% weight loss at 68 weeks (REDEFINE 1), while tirzepatide 15 mg produced approximately 22.5% at 72 weeks (SURMOUNT-1). Cross-trial comparisons have significant limitations due to differences in populations, trial design, and endpoints.

What makes cagrilintide different from pramlintide?

Both are amylin analogs, but cagrilintide represents a generational advance. Pramlintide (Symlin, approved 2005) requires three daily injections and produces only modest weight effects. Cagrilintide’s acylation strategy extends its half-life to ~7 days, enabling once-weekly injection, and its clinical weight loss data substantially exceed those observed with pramlintide.

Is cagrilintide being studied for type 2 diabetes?

Yes. The REDEFINE 2 trial specifically evaluated CagriSema in adults with type 2 diabetes, demonstrating significant HbA1c reductions (approximately 2.2 percentage points) alongside meaningful weight loss. Cagrilintide’s glucagon-suppressive and gastric-emptying effects are relevant to glycaemic control research beyond weight management alone.

References

1. Kruse T, et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. J Med Chem. 2021;64(15):11183-11194. PMID: 34288673. PubMed.
2. Fletcher MM, et al. AM833 Is a Novel Agonist of Calcitonin Family G Protein-Coupled Receptors: Pharmacological Comparison with Six Selective and Nonselective Agonists. J Pharmacol Exp Ther. 2021;377(3):417-440. PMID: 33727283. PubMed.
3. Garvey WT, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2025;393(7):623-635. PMID: 40544433. PubMed.
4. Enebo LB, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management. Lancet. 2021;397(10286):1736-1748. PMID: 33894838. PubMed.
5. Mathiesen DS, et al. Long-acting amylin analogues for the management of obesity. Curr Opin Endocrinol Diabetes Obes. 2022;29(2):183-190. PMID: 35066542. PubMed.
6. Lau DCW, et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet. 2021;398(10317):2160-2172. PMID: 34798060. PubMed.
7. Frias JP, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2023;402(10403):720-730. PMID: 37364590. PubMed.
8. Davies MJ, et al. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. N Engl J Med. 2025;393(7):636-648. PMID: 40544432. PubMed.
9. Gabe MBN, et al. Cagrilintide is not associated with clinically relevant QTc prolongation: A thorough QT study in healthy participants. Diabetes Obes Metab. 2024;26(12):5757-5766. PMID: 39279639. PubMed.
10. Verma S, et al. CagriSema Reduces Blood Pressure in Adults With Overweight or Obesity: REDEFINE 1. Hypertension. 2026;83(2):e30-e40. PMID: 41328546. PubMed.